Highly Active Cooperative Lewis Acid—Ammonium Salt Catalyst for the Enantioselective Hydroboration of Ketones

Article abstract of DOI:10.1002/anie.202012796

Enantiopure secondary alcohols are fundamental high-value synthetic building blocks. One of the most attractive ways to get access to this compound class is the catalytic hydroboration. We describe a new concept for this reaction type that allowed for exceptional catalytic turnover numbers (up to 15 400), which were increased by around 1.5–3 orders of magnitude compared to the most active catalysts previously reported. In our concept an aprotic ammonium halide moiety cooperates with an oxophilic Lewis acid within the same catalyst molecule. Control experiments reveal that both catalytic centers are essential for the observed activity. Kinetic, spectroscopic and computational studies show that the hydride transfer is rate limiting and proceeds via a concerted mechanism, in which hydride at Boron is continuously displaced by iodide, reminiscent to an S_N2 reaction. The catalyst, which is accessible in high yields in few steps, was found to be stable during catalysis, readily recyclable and could be reused 10 times still efficiently working.

Full text of DOI:10.1002/anie.202012796

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Highly Active Cooperative Lewis Acid – Ammonium Salt Catalyst
for the Enantioselective Hydroboration of Ketones
Authors: Marvin Titze, Juliane Heitkämper, Thorsten Junge, Johannes
Kästner, and René Peters
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10.1002/anie.202012796
Angewandte Chemie International Edition
RESEARCH ARTICLE
Highly Active Cooperative Lewis Acid – Ammonium Salt Catalyst
for the Enantioselective Hydroboration of Ketones
Marvin Titze,[a] Juliane Heitkämper,[b] Thorsten Junge,[a] Johannes Kästner,*[b] and René Peters*[a]
[a]
[b]
M.Sc. M. Titze, M.Sc. T. Junge, Prof. Dr. R. Peters, Universität Stuttgart, Institut für Organische Chemie, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
E-mail: rene.peters@oc.uni-stuttgart.de
M.Sc. J. Heitkämper, Prof. Dr. J. Kästner, Universität Stuttgart, Institut für Theoretische Chemie, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
E-mail: kaestner@theochem.uni-stuttgart.de
Supporting information for this article is given via a link at the end of the document.
Abstract: Enantiopure secondary alcohols are fundamental high-
value synthetic building blocks. One of the most attractive ways to get
access to this compound class is the catalytic hydroboration. We
describe a new concept for this reaction type which allowed for
exceptional catalytic turnover numbers (up to 15400), which were
increased by around 1.5-3 orders of magnitude compared to the most
active catalysts previously reported. In our concept an aprotic
ammonium halide moiety cooperates with an oxophilic Lewis acid
within the same catalyst molecule. Control experiments reveal that
both catalytic centers are essential for the observed activity. Kinetic,
spectroscopic and computational studies show that the hydride
transfer is rate limiting and proceeds via a concerted mechanism, in
which hydride at B is continuously displaced by iodide, reminiscent to
an SN2 reaction. The catalyst, which is accessible in high yields in few
steps, was found to be stable during catalysis, readily recyclable and
could be reused 10 times still efficiently working.
enantioselectivity in the hydroboration of ketones, allowing for
TONs up to 15400, being equivalent to an increase of activity of
about 1.5 to >3 orders of magnitude compared to the most
efficient asymmetric hydroboration catalysts. Our development
was driven by the idea that a Lewis acidic oxophilic metal center
could activate a ketone substrate, whereas a borane reagent
might be activated by an appended ammonium halide moiety via
a boron / halide interaction. The activated borane would thus be
quasi-intramolecularly directed towards the ketone. This
simultaneous activation of both reactants was considered as
promising tool to attain high catalytic activity,[8-10] while the
reactants were expected to be precisely spatially preorganizable
within the chiral environment of the bifunctional active site thus
enabling high levels of enantioselectivity.
Introduction
Catalytic enantioselective reductions of ketones are among the
most important asymmetric reactions owing to the significance of
enantiopure secondary alcohols as building blocks for the
synthesis of bioactive compounds.[1] An attractive class of
catalytic asymmetric reductions is the hydroboration which has
been described using various catalyst types.[2,3] A number of them
furnished products with high enantioselectivities. Probably the
most popular method of this type is the Corey-Bakshi-Shibata
(CBS) reduction of ketones which uses readily available
oxazaborolidine catalysts and H3B*L (L = THF, DMS) as
stoichiometric reducing agent and is applicable to a broad
substrate range.[4] However, despite the great progress achieved
with a number of previously reported catalyst concepts, a current
limitation still is that highly active catalysts allowing for turnover
Scheme 1. Visualization of the concept of bifunctional Lewis Acid (L.A.) –
ammonium salt catalyzed enantioselective hydroboration of ketones.
Results and Discussion
Development and Optimization Studies
As model reaction the hydroboration of acetophenone 1a by
pinacolborane (HBPin) was studied at 25 °C using Al catalyst C1
(Table 1).[11] Initial experiments conducted in CH2Cl2 proceeded
disappointingly, because only traces of racemic product were
formed like in entry 1.[12] A subsequent solvent screening
(Supporting Information) not only revealed an accelerating effect
by THF, but also allowed for high enantioselectivity (entry 2). The
use of pure THF was more efficient than a mixture of THF and
CH2Cl2 (entry 3). The use of other common hydroboration agents
led to inferior results (Supporting Information).
Continuous reaction monitoring by 1H-NMR under the conditions
of entry 2 revealed that the free alcohol 2a is generated as
catalytic intermediate, which is subsequently borylated. This
implicated that a proton source is required for catalytic turnover.
In the initial studies residual water was probably the proton source.
Various (sub)stoichiometric proton sources were evaluated
numbers
(TONs)
>500
–while
still
acting
highly
enantioselectively– remained elusive.
Some years ago we introduced the concept of asymmetric
bifunctional Lewis acid / aprotic onium salt catalysis and since
then this concept has demonstrated its potential in various
reaction classes such as [2+2] cycloadditions,[5] SN reactions[6]
and 1,2-additions.[7] The synthetic transformations investigated
were either previously not viable or not very efficient in terms of
catalytic activity. Herein we report that this concept allows for
extraordinary
catalytic
activity
combined
with
high
1
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10.1002/anie.202012796
Angewandte Chemie International Edition
RESEARCH ARTICLE
identifying iPrOH as the most efficient one of those examined (see
Supporting Information). By this the yield was strongly improved
(entry 4). Additional improvements were achieved by an excess
of HBPin (entry 5) and an increased concentration. This allowed
to significantly reduce the catalyst loading to technically
interesting values (entries 6-11). With 0.05 mol% of C1 an ee of
97% in combination with a nearly quantitative product yield was
attained (entry 7).[13] However, under these optimized conditions,
attractive results were also attained with just one equivalent of
HBPin (entry 8). Also, with as little as 0.01 and 0.005 mol% C1 –
i.e. 100 ppm and 50 ppm catalyst, respectively– high ee values
(92% and 91%) and good yields (93% and 77%) were noticed
(entries 9 & 10), corresponding to TONs of 9300 and 15400,
respectively. These values are substantially higher than for all
previously reported highly enantioselective catalysts in this
reaction type.[2] The reaction was also performed under neat
conditions and similar results were attained (entry 11).
on the aromatic moieties. In case of 2k a basic reaction work-up
was required to avoid racemization of the product.
Chemoselectivity problems were not found with functional groups
that are also susceptible to reductions. In addition, extended π-
systems such as 2-naphthyl (→ 2m) were successfully used. Next
to methyl ketones, other alkyl ketones (→ 2n-2r) as well as
heteroaryl ketones (→ 2s & 2t) were accommodated and allowed
for good to high enantioselectivity.
Table 2. Investigation of different ketone substrates 1.[a,b]
Table 1. Development of the title reaction.
#
C1/
solvent
[1a]/ HBPin/ iPrOH/ yield[a]/ ee[b]
/
TON
mol%
mol/L equiv. equiv.
%
%
1
5
5
CH2Cl2
THF
0.14
0.14
1.0
1.0
1.0
1.0
2.0
2.0
2.0
1.0
2.0
2.0
2.0
-
2
2
0.4
4.8
3.2
2
3
4
5
6
7
8
9
-
24
16
52
72
99
99
84
93
77
72
94
93
5
CH2Cl2/THF (2:1) 0.14
-
5
THF
THF
THF
THF
THF
THF
THF
THF
0.14
0.14
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
92 10.4
92 14.4
95 198
97 1980
93 1680
92 9300
91 15400
91 14400
5
0.5
0.05
0.05
0.01
1.0
1.0
1.0
10 0.005
11 0.005
1.6
neat
[a] Yield determined by 1H-NMR of the crude product using an internal standard.
[b] Enantiomeric excess determined by GC.
Reaction Scope
The reaction conditions of Table 1/entry 7 were then applied to
different prochiral ketones (Table 2). Ortho-, meta- and para-
chloro substituted aryl rings within alkyl aryl ketones were all well
tolerated and provided 2b-2d. Next to other σ-acceptors like p-
fluoro (→ 2e) and π-acceptors like p-nitro (→ 2f), p-cyano (→ 2g),
a p-methylester (→ 2h) and a p-dimethylamide group (→ 2i), also
σ-donors like p-methyl (→ 2j) as well as π-donors like p-methoxy
(→ 2k) and even unprotected p-amino (→ 2l) were well accepted
[a] Yields of isolated products. [b] The enantiomeric excess was determined by
HPLC or GC. [c] 0.1 mol% of C1 were used. [d] 0.2 mol% of C1 were used. [e]
2
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10.1002/anie.202012796
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RESEARCH ARTICLE
0.5 mol% of C1 were used. [f] 1.0 mol% of C1 were used. [g] Basic work-up
In total 11 runs were conducted. Taking advantage of the
ammonium salt moiety within the catalyst, n-pentane was added
to the reaction mixture after 22 h in order to precipitate C1, which
was then washed, dried under high vacuum, and reused. For the
first 9 runs, nearly quantitative yields were achieved. The ee
slowly dropped from 95 to 91%. Starting from the tenth run, the
yield started to decrease (81% for run 10, 75% for run 11).
Nevertheless, the enantiomeric excess stayed above 90%. Albeit
these results have not been optimized regarding the catalyst
reisolation, they show that C1 is remarkably stable during the
reaction and also during recovery thus further increasing the
practicality of the title reaction.
using sat. NaHCO3. [h] Neutral work-up using water.
Noteworthy is also that dialkyl ketones can be efficiently used, if
the difference of the steric demand of both residues is sufficiently
large. 2u was thus formed in almost quantitative yield with 98%
ee. Like expected with decreasing size difference the
enantioselectivity decreased (→ 2v & 2w). A similar effect was
observed for enones like shown for 2x, 2y and 2z. The latter has
been reported as intermediate toward a number of carotenoid-
derived odorants and bioactive terpenes including α-
damascone.[14]
Upscaling and Catalyst Recycling
The model reaction was also investigated on a gram scale (Table
3). With 0.05 mol% of catalyst and around 1 g of substrate, the
product was formed with high yield (97%) and enantioselectivity
(ee = 96%, entry 1). To enforce a quantitative yield, a reaction on
10 g scale was run with prolonged reaction time and provided
excellent results (entry 2). A gram scale experiment was also
performed employing only 0.02 mol% of catalyst (entry 3). Also in
Mechanistic Studies
a) Control Experiments
To learn more about the role and impact of the catalytically
relevant groups in C1, experiments with several control catalyst
systems were conducted. Regarding the Lewis acidic center,
catalysts with different anionic ligands were investigated (Table
4). Next to C1 bearing a chloride ligand also the corresponding
fluoride (C2) and methyl (C3) containing complexes were
employed. It was found that C1 was significantly more efficient
regarding productivity and enantioselectivity. In particular C3 was
found to be a poor catalyst. In combination with the solvent effect,
an explanation of the exceptionally high activity of C1 might be
that the catalytically active species makes use of a cationic Al
center by displacing the metal bound chloride with THF (see also
DFT calculations below). Cationic Al salen and salphen catalysts
lacking an ammonium functional group and bearing two
coordinating THF molecules at the Al center were previously
found and structurally characterized by Coates et al.[15] Because
the Al-F bond in C2 is much stronger than the Al-Cl bond,[7] the
generation of the cationic species is less favored. In addition,
neither Me in C3, nor the isopropoxide formed by protonation of
C3 with isopropanol are expected to readily form a cationic Al
center.
this case,
a
quantitative yield (TON 4950) and high
enantioselectivity were attained (ee = 96%). These results
demonstrate the practical utility of this method.
Table 3. Scale-up results.
scale 1a/
C1/
t/ yield[a]
/
amount 2a/ ee[b]
/
#
TON
g (mmol)
mol%
d
%
97
99
99
g
%
96
96
95
1
2
3
1.00 (8.35)
1.00 (8.35)
0.05
0.02
0.05
1
0.99
1.01
10.14
1860
4950
1980
4.5
4.5
10.03 (83.50)
[a] Yield of isolated product. [b] Enantiomeric excess determined by GC.
Table 4. Comparison of anionic ligands at the Al center.
In addition, the possibility to recycle the catalyst was examined
(Chart 1).
Chart 1. Catalyst recycling studies.[a,b]
Yield
93
ee
91
100
80
60
40
20
0
96
95
95
94
92
91 91 91 91
81
#
C
yield[a]
%
/
ee[b]
/
%
75
99 99 99 99 99 99 99 99 99
1
2
3
C1
C2
C3
99
42
14
97
80
27
1
2
3
4
5
6
7
8
9
10 11
run
[a] Yield determined by 1H-NMR of the crude product using an internal standard.
[b] Enantiomeric excess determined by GC.
[a] Yield determined by 1H-NMR of the crude product using an internal standard.
[b] The enantiomeric excess was determined by GC.
3
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10.1002/anie.202012796
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RESEARCH ARTICLE
Upon treatment of C1 with an excess of HBPin, in-situ recorded
IR, 1H-NMR and UV-Vis spectra did not result in significant
changes. A similar result was also found for catalyst treatment
with iPrOH in UV-Vis experiments (Supporting Information). The
formation of significant amounts of Al-H or Al-OiPr species thus
seem unlikely.
was found for chloride. However, the observed effect is small
(around 0.05 ppm), probably due to the remote position of the
investigated Me group.
Using 0.5 equiv. of TBACl, there was no second signal for free
HBPin, but the observed shift was smaller pointing to a dynamic
behaviour for the chloride coordination. Also at 20 °C there was
a single signal, but the observed shift was larger, pointing to more
halide adduct in the equilibrium.
In addition, we investigated the variation of the ammonium
counterion in the bifunctional complexes under the optimized
conditions (Table 6). C1 (entry 1) offered the best productivity for
this catalyst series. Using C1-Br and C1-Cl bearing bromide and
chloride counterions, respectively, the product yields were
reduced by around 30%. Using a ‘non’-nucleophilic ion the
productivity was further decreased but remained noticeable. This
seems contra-intuitive, but might be explained by the generation
of a cationic Al center thus releasing a nucleophilic chloride, while
the non-nucleophilic anion is not expected to strongly interact with
the cationic Al center.
To learn more about the importance of the ammonium halide
moiety, different sets of experiments were performed. In the initial
set, various tetrabutylammonium salts were examined as
catalysts to study the effect of the anion. Using the conditions of
Table 1, entry 7, but in the absence of a catalyst, racemic product
was formed in 13% yield after 22 h at 25 °C (Table 5, entry 1).
Employing different halide salts, catalytic activity increased with
increasing size and thus higher polarizability of the anion (entries
3-5). In contrast to this trend, the highest activity was found with
fluoride. However, we found that treatment of HBPin with TBAF
results in partial formation of BF3 and TBA[B(Pin)2]. This outcome
was confirmed by X-ray crystal structure analysis (see Supporting
Information).[16,17] BF3 might thus act as a Lewis acid cocatalyst
which increases the catalytic activity.
Table 6. Study of the impact of different counterions in catalysts C1.
A lower yield was found for less nucleophilic anions like triflate.
Decreasing the TBAI loading from 1.0 to 0.05 mol% resulted in
decreased activity. These results demonstrate that ammonium
halides have a catalytic activity in the reduction. Nevertheless,
with TBAI the catalytic activity is significantly lower than for
catalyst C1 also bearing an iodide counterion (compare Table 5,
entry 6 to Table 1, entry 6-9). This confirms the importance of the
Lewis acidic Al center.
Table 5. Control experiments with TBAX salts.
#
1
Catalyst
C1
yield[a]/ %
ee[b]/ %
97
#
TBAX,
X =
TBAX/
mol%
yield[a]
%
/
99
69
67
57
2
C1-Br
C1-Cl
C1-PF6
95
[b]
1
2
3
4
5
6
7
-
-
1
13
99
37
55
38
81
37
3
93
F
Cl
Br
OTf
I
4[c]
92
1
[a] Yield determined by 1H-NMR of the crude product using an internal standard.
[b] The enantiomeric excess was determined by GC. [c] The corresponding
triethylammonium salt was used in the catalyst.
1
1
Since the catalytic activity employing the different halide ions is
not in agreement with the proposed binding tendencies of chloride,
bromide and iodide to HBPin, it seems that the formation of an
anionic halide/HBPin adduct intermediate cannot account for the
catalytic activity differences. DFT calculations disclosed below
suggest that interaction of the halide anion with the B center and
the transfer of the hydride to the carbonyl group is a concerted
process, reminiscent to an SN2 reaction thus continuously
displacing hydride by halide. Formation of an anionic intermediate
is thus not necessary. Like in an SN2 reaction, polarizability is a
decisive factor (see also Figure 5).
Additional control experiments were performed with the widely
applicable salen catalyst C4[18] (Table 7). As shown in entry 1, in
the absence of any catalyst and iPrOH, only traces of product
were formed. In the presence of iPrOH (1 equiv.), the yield raised
to 13% (entry 2). The same conditions, but using 0.05 mol% of
catalyst C4, 16% of 2a were formed with an ee of 72% (entry 3).
1
I
0.05
[a] Yield determined by 1H-NMR of the crude product using an internal standard.
[b] No catalyst was used.
The interaction between halide ions and the boron center –maybe
resulting in a more pronounced hydride character of HBPin– was
studied by H-NMR (for details see the Supporting Information).
1
The methyl signal of the pinacolate framework was used as probe,
because the hydride signal itself was quite broad. For the same
reason, also 11B-NMR was not employed. By adding the
corresponding TBA halide salt (1 equiv.) to HBPin in DCM-d2 at
25 °C, the signals were slightly upfield-shifted, arguably as a
result of a higher electron density at the B center. The softer the
halide ion, the smaller should be the interaction with the relatively
hard B center. According to these expectations the highest shift
4
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10.1002/anie.202012796
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RESEARCH ARTICLE
With 0.005 mol%, 13% of product were obtained (entry 4) with an
ee of 49%, probably because the background reaction gained
importance (compare to entry 2). These experiments show that
catalyst C4 lacking an internal ammonium moiety is significantly
less active and acts less enantioselectively than the bifunctional
catalyst C1. C4 is also less active than TBAI (0.05 mol%, entry 5).
With the binary system of C4 and TBAI (entry 6), results became
slightly better as compared to the use of C4 only (entry 3).
Nevertheless, the productivity was lower than with the TBAI alone
(entry 5). These results show that the bifunctional catalyst is
substantially more efficient than monofunctional Lewis acid or
ammonium catalysts and the corresponding binary catalyst
system, probably as result of an intramolecular double activation
pathway.
profiles of experiment 1 and 3 and the acceleration of experiment
3 compared to experiment 2 demonstrate two things:
1) There is apparently no significant catalyst decomposition taking
place, because otherwise the reaction rate of experiment 2 and 3
should be higher than that of experiment 1.
2) As the reaction rate of experiment 3 is higher than that of
experiment 2, the product 2a has an accelerating effect. It is likely
that 2a also acts as a proton source to release the product (see
below).
Table 8. Initial reaction conditions for the RPKA “same excess” experiments.
Table 7. Control experiments with catalyst C4.
Exp.
[1a]/
mol/L
[HBPin]/
mol/L
[iPrOH]/
mol/L
[2a]/
mol/L
1
2
3
0.84
0.42
0.42
1.68
1.26
1.26
0.84
0.42
0.42
0
0
0.42
0,80
Exp. 1
Exp. 2
Exp. 3
#
C4/
mol%
TBAI/
mol%
iPrOH/
equiv.
yield[a]
%
/
ee[b]
/
%
0,70
0,60
0,50
0,40
0,30
0,20
0,10
0,00
1
2
3
4
5
6
0
0
0
0
1
1
1
1
1
2
-
-
0
13
16
13
37
25
0.050
0.005
0
0
72
49
-
0
0.05
0.05
0.050
74
0,00
1,00
2,00
3,00
4,00
t/ d
[a] Yield determined by 1H-NMR of the crude product using an internal standard.
[b] The enantiomeric excess was determined by GC.
Figure 1. Reaction profiles of 1a using Blackmond’s “same excess” protocol
under the conditions of Table 8.[19]
b) Kinetic Investigations
Reaction monitoring and kinetic investigations were performed via
1H-NMR spectroscopy in THF-d8 at 25 °C using 0.1 mol% of C1
(for details of the kinetic studies see the Supporting Information).
Catalyst robustness and a possible product inhibition were
investigated by Blackmond’s Reaction Progress Kinetic Analysis
(RPKA) “same excess” protocol.[19] Three experiments were
performed using different initial concentrations (Table 8,
Figure 1).[20]
The decay of the concentration of 1a over the course of the
reaction is shown. Experiment 1 (Table 1) serves as reference
reaction. In experiment 2 the starting concentration of 1a
corresponded to that of the reference reaction experiment when
the latter had reached 50% conversion.[19] The time shift of the red
curve shows, that in experiment 2 the reaction proceeded slower
than in experiment 1. In a further experiment 3 the starting point
of experiment 2 was used except that 50 mol% of product 2a was
added, because in reference experiment 1 also 50% product were
present after 50% conversion. The good overlay of the reaction
The empirical rate law was determined by the Variable Time
Normalization Analysis (VTNA) described by Burés.[21] Again, the
model reaction of 1a was examined at 25 °C in THF-d8 using
catalyst C1. Six reactions with different initial concentrations of 1a,
C1, HBPin, iPrOH and 2a were used monitoring the concentration
of all reagents (for details see the Supporting Information).
The best fit for the normalization of the time scale axis was
achieved for the following empirical rate:
r = kobs [C1]1.00 [1a]1.00 [HBPin]0.52 [iPrOH]0.37 [2a]0.31
.
The reaction rate thus follows a first order kinetic dependence for
catalyst C1[22] and the substrate 1a, whereas for HBPin, iPrOH
and 2a orders between 0 and 1 were found.[23] The first order
kinetic in catalyst indicates that a single catalyst molecule is
probably involved in the turnover-limiting step. To probe this
5
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10.1002/anie.202012796
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RESEARCH ARTICLE
t
interpretation we took account of a non-linear effect.[24] As
expected, a linear correlation between catalyst ee and product ee
values were found thus confirming this claim (see Supporting
Information).
studied, where the two Bu groups of C1 in para-position to the
oxygen were removed to simplify the model.
The quantum chemical investigations predict a mechanism
proposed in Figure 3. It turns out that step I, in which the hydride
of the borane is transferred to the ketone and the borane binds to
the free iodide, is rate determining. With the Al-Cl catalyst C1S,
this step has a barrier of 102 kJ mol-1, which is too high to explain
the observed kinetics. Thus, C1 is not expected to be the active
catalytic species. In agreement with the experimental finding that
THF is required for the reaction to proceed, we found that a
replacement of the chloride by THF is necessary to form an active
catalyst C1+. Figure 2 shows a simplified geometry of this complex
(C1SS+), where the tBu groups and the onium moiety are removed
As both alcohols accelerate the reaction, they are likely to cause
the protonation step during the catalytic reaction. By the
concentration profiles of 1a and the corresponding boric-acid
esters 2a-BPin and iPrO-BPin this assumption is reinforced (see
Supporting Information). There is also an uncatalyzed side
reaction taking place, in which HBPin reacts with iPrOH to form
the corresponding boric acid ester, which constantly reduces the
concentration of both iPrOH and HBPin. This event thus slows
down the overall reaction progress.
Based on the described experimental results, we propose the
simplified catalytic cycle described in Scheme 2.
(
for twice simplified). The exchange releases the chloride,
ss
which could subsequently also take over the role of the
nucleophilic iodide in the catalytic cycle. This explains that some
activity was observed with C4, lacking the onium moiety and the
iodide, as well as catalyst systems with ‘non’-nucleophilic ions like
C1-PF6.
+
The reaction barrier with the THF-activated catalyst C1S is
significantly lowered to 62 kJ mol1. It should be noted that
according to DFT, C1S is lower in energy by 20 kJ mol1 than C1S
.
+
However, the high excess of the solvent shifts the equilibrium
towards the active form.
To explain the observed reactivity, structurally simplified
complexes of the active (C1SS+) and the original (C1SS) catalyst
(see Figure 2) were investigated with the help of DFT and Intrinsic
Bond Orbitals (IBOs) (see Computational Details). IBOs are
helpful to interpret quantum chemical calculations, as they often
provide chemically meaningful orbitals.
For C1SS+, the bond length Al-O (THF) was 1.87 Å. The localized
IBO, which is responsible for this bond, is located at aluminum by
only 12% of its charge. In C1SS the corresponding Al-Cl bond
length is 2.17 Å. In this case 19% of the bond charge is located at
aluminum. As a consequence, the aluminum center carries a
higher partial charge (IBO charge) of +1.19 in C1SS+ than in C1SS
(+1.08). Therefore, as expected the Lewis acidity of the aluminum
is increased by the exchange of chloride with THF.
Scheme 2. Proposed simplified catalytic cycle.
Acetophenone 1a is expected to coordinate to the Lewis acidic
aluminum center, which is suggested to be cationic in THF in the
catalytically most active form A in agreement with studies of
Coates and the above described solvent effect.[15] A cationic Al
complex lacking the coordinated ketone substrate was indeed
detected by ESI mass spectrometry using catalyst reisolated after
a catalytic run. Moreover, our DFT studies presented below show
that the activation barrier is significantly lower with a cationic
compared to a neutral Al center. The iodide counterion of A
(alternatively a released chloride ion) could activate and direct
HBPin quasi-intramolecularly towards the keto moiety to generate
Al-alcoholate B and IBPin (alternatively ClBPin). Protonation of B
by iPrOH could release alcohol 2a, whereas the generated
isopropanolate could be trapped by IBPin (alternatively ClBPin).
Upon accumulation of 2a, it can also serve as proton source like
iPrOH to release more of 2a, while itself being transformed to the
final boric ester product 2a-BPin. Coordination of another
acetophenone molecule would close the catalytic cycle.
Figure 2. The binding IBO for [C1SS+]Cl- (left) and C1SS (right). For a color figure
see the Supporting Information.
+
The resulting mechanism with C1S and its energetics are
illustrated in Figure 3. The structures of the respective transition
states can be found in Figure 4. We provide the energies for the
unimolecular steps only, since the free-energy of association is
rather ill-defined at our level of treatment of the solvation
(COSMO) and in any case depends on the concentration of the
reaction partners.
As already mentioned, step I from A to B represents the rate
determining step of the catalytic mechanism with a barrier of
62 kJ mol-1. It describes the carbonyl reduction via a hydride
c) Computational Investigations
To gain more insight into the reaction mechanism, the reduction
of 1a with HBPin was investigated by density functional theory
(DFT) at the M06-2X/def2-TZVP level of theory on M06-2X/def2-
SVP geometries with solvent effects accounted for by the
conductor-like screening model (COSMO, see Computational
Details). The catalytic mechanism with C1S (s for simplified) was
6
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10.1002/anie.202012796
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RESEARCH ARTICLE
transfer from the borane to the electrophilic center of the ketone,
which is activated by the Lewis-acidic aluminum. In a concerted
reaction the borane simultaneously binds to the free iodide.
An electronic effect of the iodide on the borane was also studied.
The B-I distance in A (before the bond formation) is 3.56 Å and
decreases to 2.45 Å in TSAB and further to 2.14 Å once the B-I
bond is formed in B. An analysis of the IBOs reveals that there
already is a slight interaction between the iodide and the borane
in A. Figure 5 shows that the electron density of one IBO, that
relates to the free electron pair at the iodide, is polarized towards
the borane. The role of the iodide, through the help of the onium
moiety, is not only to be in the proximity of the HBPin to act as a
binding partner as soon as the hydride is transferred, but might
also push electron density towards the borane activating the
hydride.
Figure 3. Details of the catalytic steps as obtained from DFT with relative free-energy profile of the reaction steps A  B (step I) and B+iPrOH  C (step II). Dashed
lines represent bimolecular steps.
As the enantioselectivity is here defined in the rate determining
step, the formation of the enantiomer with minor yield is also
studied. It yields a barrier of 74 kJ/mol. The enantiomeric excess
can be calculated based on these results to be 98% which is in
very good agreement with the measured ee value of 97%.
As a consequence, the Al-O bond length increases from 1.80 Å to
2.00 Å.
Figure 5. IBOs that relate to the p electron pairs of the iodine in A. Two electron
pairs have two equally sized lobes (one of them is shown on the left) and one is
polarized towards the borane (right). For a color figure see the Supporting
Information.
Figure 4: Geometries of the transition states obtained by DFT. Lengths of the
bond that are formed or broken during the transition are given in Å. For a color
figure see the Supporting Information.
The step possesses an early transition state with a small barrier
of 8 kJ mol-1. To confirm the experimentally found kinetics, where
the product alcohol takes over the role of a protonating agent
during the course of the reaction, step II was also investigated
with the product alcohol 2a instead of iPrOH. Apart from slightly
more steric hindrance the reaction is qualitatively the same. The
In step II an iPrOH molecule is added (B+iPrOH) and the
alcoholate that is coordinated to the aluminum center protonated.
7
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10.1002/anie.202012796
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RESEARCH ARTICLE
barrier increases to 16 kJ mol1 but is still very small. When iPrOH
is consumed in the course of the reaction and the concentration
of the product alcohol increases, it is likely that the latter will be
the more and more dominating proton source.
the IBOs was realized using the IboView program by Knizia
(http://www.iboview.org/).
To estimate the reliability of the DFT results, single point
calculations have been repeated with the functionals TPSS and
PBE0 (see Supporting Information). They result in overall smaller
barriers but the conclusions drawn from DFT are unaltered.
Acknowledgements
This work was financially supported by the Deutsche
Forschungsgemeinschaft (DFG, PE 818/8-1, project 404194277).
We thank Dr. Wolfgang Frey for determining and analyzing an X-
ray crystal structure analyses (see ref. [17]). J. H. acknowledges
financial support in the form of a PhD scholarship from the
Studienstiftung des Deutschen Volkes (German National
Conclusion
In summary, we have reported a concept for the catalytic
asymmetric hydroboration of ketones, which allows for
extraordinarily high turnover numbers (up to 15400) that are
around 1.5 - 3 orders of magnitude higher than with the most
efficient catalysts previously reported. The chiral secondary
alcohols –high-value-added products– were typically formed with
high yields and high enantioselectivity. In our concept an aprotic
ammonium halide moiety and an oxophilic Lewis acid work in
concert and cooperate with each other within the same catalyst
molecule. This was confirmed by a number of control experiments
showing that both catalytic centers are indispensable for the
observed activity. Moreover, kinetic, spectroscopic and
computational studies revealed that the hydride transfer is most
likely rate limiting. According to our calculations, it proceeds via a
concerted mechanism, in which hydride is continuously displaced
by iodide at the B center, reminiscent to an SN2 reaction.
Simultaneously, the hydride attacks the ketone, which is activated
by a cationic Al(III) center. Further practical value is added by the
fact that the catalyst, which is readily accessible in high yields in
few steps, is stable during catalysis and readily recyclable by
taking advantage of the ammonium salt moiety. This allowed to
reuse the catalyst 10 times, while still efficiently working.
Academic
Foundation).
We
thank
the
Deutsche
Forschungsgemeinschaft (DFG, German Research Foundation)
for supporting this work by funding EXC 2075 - 390740016 under
Germany’s Excellence Strategy. The authors acknowledge
support by the state of Baden-Württemberg through bwHPC and
the German Research Foundation (DFG) through grant no INST
40/467-1 FUGG (JUSTUS cluster).
Keywords: ammonium salts • asymmetric catalysis • chiral
alcohols • cooperative catalysis • hydroboration
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9
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RESEARCH ARTICLE
Entry for the Table of Contents
A new concept for asymmetric hydroboration of ketones is shown, in which an ammonium halide initiates a hydride transfer to a
Lewis acid activated ketone. Advantages of the bifunctional catalyst include remarkable turnover numbers (up to 15400, 50 ppm
catalyst) and high enantioselectivity. The catalyst was recycled 10 times still providing high efficiency. Mechanistic and DFT studies
confirm the cooperative mechanism.
10
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